Biomarker Hunt Gains Traction Among Therapeutic Advances in HCC

David J. Pinato, MD, PhD

The explosion of novel agents that are approved and in the pipeline for the treatment of patients with hepatocellular carcinoma (HCC) has opened the door for future biomarker developments, explained David J. Pinato, MD, PhD.

"This is a moment of dramatic change in HCC care," said Pinato. "[The lack of biomarkers] was [a result of] a vicious circle. Patients were not routinely biopsied because there were no alternative therapies to offer them. That led to a lack of updated knowledge of the molecular pathophysiology of liver cancer. Then, that led to a lack of biomarkers for these patients."

Nevertheless, the hunt continues to determine optimal markers that could predict response to the growing number of therapies, he added. Beyond PD-L1 expression for immunotherapy, another potential target being explored is FGF19 expression. Multi-technology approaches could also help identify which tumors respond best to immunotherapy or antiangiogenic agents alone or in combination.

In an interview with OncLive during the 2020 HCC-TAG Conference, Pinato, a clinical senior lecturer in medical oncology, clinician scientist, and consultant medical oncologist in the Department of Surgery and Cancer at Imperial College London, highlighted the clinical and biological challenges in identifying biomarkers in HCC and the potential introduction of biomarkers in the future.

OncLive: What is the clinical need for biomarkers in HCC?

Pinato: HCC has been characterized by a number of failures, which have been focused around phase III developments. Obviously, a lot of money went into planning clinical trials to show superiority over standard of care in both the first- and second-line settings.

Up until recently, there was a decade of stagnation in drug development in HCC. That decade cost a lot of money and led to numerous delays in terms of providing new therapies for HCC.

Part of the problem is the fact that we are lacking a good platform of biomarkers that could help us select patients who may respond better to a particular molecular therapy versus another.

This issue is becoming more relevant now as new therapies with novel mechanisms of action [are being introduced]. We saw the results of the IMbrave150 trial with atezolizumab (Tecentriq) and bevacizumab (Avastin) in the frontline setting for patients with HCC. [Those data] are reshaping the standard of care. Additionally, PD-1 inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), are reshaping what is available for patients with HCC.

Yet, both in clinical practice and research, we are not guided by biomarkers. Features in either the tumor or biologic material can potentially predict how to best use these treatments.

What biomarkers are currently under investigation in HCC?

In terms of treatments with TKIs, there have been a number of studies trying to look at functional genomic approaches, such as tumor sequencing and transcriptomic sequencing of pretreatment tumor samples, that are emerging both from observational studies, as well as large phase III studies that led to the approval of therapies like sorafenib (Nexavar) and regorafenib (Stivarga).

Unfortunately, these studies have used high throughput technologies to try and understand the disease features on the basis of sequencing data that would scale with the presence of response or refractoriness to 1 particular type of therapy.

For the traditional TKIs, such as sorafenib and regorafenib, we haven't seen a lot of progress. This is mostly because these treatments are untargeted, and we don't know how to best select patients for these therapies.

There have also been molecularly driven studies with tivantinib or fisogatinib, for example, which has looked at FGF19 expression as a potentially novel biomarker.

The experience of fisogatinib with FGF19 expression stands out because it is the first time that we have seen the potential for 1 immunohistochemical marker to enrich responses to a specific targeted anticancer therapeutic.

Immunotherapy is an expanding therapeutic modality. PD-1 expression has been looked at as a potential biomarker of response. This is on the backdrop of PD-1 immunohistochemical expression being a companion diagnostic in other oncologic indications, such as non-small cell lung cancer (NSCLC). However, this has not been predictive of outcomes in HCC.

We ran a study at Imperial College London called Blueprint-HCC, in which we looked at the different platforms that have been used to test for PD-L1 expression. From that study, we showed that there is a lot of heterogeneity in the way PD-L1 is detected across antibodies.

The future will be to invest in multi-technology approaches to determine which tumors will respond best to antiangiogenics alone, which ones will have intermediate benefit and may respond to either antiangiogenics or immunotherapy, or which tumors are exclusively sensitive to immunotherapy. That is, unfortunately, not available yet.

What makes HCC a uniquely difficult disease to identify predictive biomarkers for?

First of all, HCC has been dominated by 1-and only 1-molecular therapy for the past 10 years. There was no alternative, on clinical grounds, that would justify the use of molecular biomarkers or even investigations with invasive procedures like biopsies. That is a purely clinical reason.

There are also biological reasons. From a genomic point of view, HCC has been fully dissected into many subclasses, but those have been largely descriptive. There is a lack of actionable drivers.

In other disease areas, there are very specific mutations that are driving the progression of malignancies in a subpopulation of patients, such as ALK translocations in NSCLC, for example. In HCC, this does not happen, so it is particularly difficult to see biomarkers being implemented.

It is also true that the presence of very effective radiologic criteria for the diagnosis of HCC has led most institutions to abandon the process of performing routine biopsies for patients.

With the influx of novel agents in this space, will biopsy become a more routinely implemented tool?

That is likely to happen. The effort of trying to identify biomarkers in HCC has to be driven by a joint collaboration between academia and industry, which sometimes have opposing interests.

These 2 worlds have to come together because, ultimately, if the progress keeps up at this current pace, it will clearly be a question of which patient will be most appropriately suited for first- and second-line therapy.

This will have a huge impact in clinical trial design, as well. Even pharmaceutical companies will benefit from knowing a bit more about the molecular makeup of patients with HCC, provided we are able to jointly form that linkage between biomarker and clinical outcome of interest.

Moving away from biomarkers, how do you currently determine sequencing with these novel agents? Will sorafenib retain a role in HCC treatment?

As far as we know, atezolizumab/bevacizumab has shown superiority over sorafenib. This is the very first study that has met all the predefined endpoints of overall survival (OS), progression-free survival, overall response rate, and patient-oriented outcomes. There is a host of evidence to suggest that this particular combination will exert transformative changes in the care of patients with advanced HCC.

There are a number of clinical trials due to report in the near future. In particular, some of these trials are looking at immunotherapy doublets with PD-1/CTLA-4 inhibitors. Most of these trials will be reporting on first-line use, so it is likely that the frontline space will become crowded in the next few months to years.

TKIs will always inevitably play a role in treating patients with HCC; however, the positioning of these agents will likely shift on the basis of duration of response, likelihood of response, and extent of clinical benefit for the patient.

There is a lot of discussion as to how the introduction of combination immunotherapy may shift the use of TKIs across later lines of therapy. This is reasonable and something that we have seen in other oncological indications, such as renal cell carcinoma where initial interferon and bevacizumab was the first-line treatment, then it was shifted down progressively, and then it eventually phased out.

It depends on what the new approvals will be and the role of the regulatory bodies in terms of picking up the approvals across the globe.

What is the importance of utilizing a multidisciplinary approach in treating patients with HCC?

It is absolutely crucial that we have an ongoing multidisciplinary effort in managing patients with HCC. These patients often shift from locoregional or radical care to palliative care in terms of potentially initiating systemic therapies.

As new treatment options become available, we are going to see that the link between good management of the underlying liver function, as well as good oncologic management from locoregional and systemic perspectives is important.

We are all here to maximize oncological outcomes for patients. OS is key in this; I don't think incremental improvement is going to be seen unless we keep working together as we have done so far.

Historically, we have never been in a phase where there is a lot of academic, clinical and pharmaceutical interest in HCC. Education is key. It is important that those involved in the care of patients with HCC speak out and share their knowledge with others, so we can continue expanding this community and ultimately, benefit our patients.

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